ABSTRACT

Context Acute lower respiratory tract infection is the most common condition
treated in primary care. Many physicians still prescribe antibiotics; however,
systematic reviews of the use of antibiotics are small and have diverse conclusions.

Objective To estimate the effectiveness of 3 prescribing strategies and an information
leaflet for acute lower respiratory tract infection.

Design, Setting, and Patients A randomized controlled trial conducted from August 18, 1998, to July
30, 2003, of 807 patients presenting in a primary care setting with acute
uncomplicated lower respiratory tract infection. Patients were assigned to
1 of 6 groups by a factorial design: leaflet or no leaflet and 1 of 3 antibiotic
groups (immediate antibiotics, no offer of antibiotics, and delayed antibiotics).

Intervention Three strategies, immediate antibiotics (n = 262), a delayed
antibiotic prescription (n = 272), and no offer of antibiotics (n = 273),
were prescribed. Approximately half of each group received an information
leaflet (129 for immediate antibiotics, 136 for delayed antibiotic prescription,
and 140 for no antibiotics).

Main Outcome Measures Symptom duration and severity.

Results A total of 562 patients (70%) returned complete diaries and 78 (10%)
provided information about both symptom duration and severity. Cough rated
at least “a slight problem” lasted a mean of 11.7 days (25% of
patients had a cough lasting ≥17 days). An information leaflet had no effect
on the main outcomes. Compared with no offer of antibiotics, other strategies
did not alter cough duration (delayed, 0.75 days; 95% confidence intervals
[CI], −0.37 to 1.88; immediate, 0.11 days; 95% CI, −1.01 to 1.24)
or other primary outcomes. Compared with the immediate antibiotic group, slightly
fewer patients in the delayed and control groups used antibiotics (96%, 20%,
and 16%, respectively; P<.001), fewer patients
were “very satisfied” (86%, 77%, and 72%, respectively; P = .005), and fewer patients believed in the
effectiveness of antibiotics (75%, 40%, and 47%, respectively; P<.001). There were lower reattendances within a month with antibiotics
(mean attendances for no antibiotics, 0.19; delayed, 0.12; and immediate,
0.11; P = .04) and higher attendance with
a leaflet (mean attendances for no leaflet, 0.11; and leaflet, 0.17; P = .02).

Conclusion No offer or a delayed offer of antibiotics for acute uncomplicated lower
respiratory tract infection is acceptable, associated with little difference
in symptom resolution, and is likely to considerably reduce antibiotic use
and beliefs in the effectiveness of antibiotics.

Figures in this Article

Acute lower respiratory tract illness is the most common condition treated
in primary care.1,2 Assuming 75%
of patients are prescribed antibiotics1 and
using conservative national morbidity survey estimates,2 acute
cough costs the UK National Health Service at least US $270 million in consultation
costs and US $35 million to 70 million antibiotic prescription costs annually.
In the United States, excess antibiotic prescribing is mainly for pharyngitis
and acute bronchitis, amounting to 55% of prescriptions and costing $726 million
per year.3

A consensus has been made for limiting antibiotic use in acute lower
respiratory tract infection.4- 6 However,
recent systematic reviews7,8 have
come to diverse conclusions about the likely effectiveness of antibiotics,
and the most recent Cochrane review7 confirms
a moderate effect of antibiotics on illness course; the debate continues unabated
about the role of antibiotics because these reviews are relatively small (9
trials of 750 patients7). There are also concerns
about complications if antibiotics are not prescribed9,10 and
debate about which clinical characteristics identify those patients at higher
risk.11- 14

Although double-blind placebo-controlled trials are important to assess
efficacy, open trials help assess effectiveness and are vital when outcomes
include patient perceptions, beliefs, satisfaction, and return rate to the
physician’s office15; only if patients
know that they are not getting antibiotics initially can the impact on beliefs,
antibiotic use, and behavior of either not prescribing or delayed prescribing
be realistically assessed. By using simple-structured support and advice for
each group, in effect generating a placebo effect in each group, any placebo
effect related to prescribing antibiotics can be minimized.15

Prescribing strategies to treat upper respiratory tract illness, which
do not involve initial antibiotics (either no antibiotics or offering delayed
antibiotics), are effective in 70% to 90% of cases, result in acceptable symptom
control, are satisfactory to the patient,15 and
can reduce reconsultation by up to 40%, with the delayed approach having the
lowest reattendance rates.16 It is unclear
whether these findings can generalize to lower respiratory tract infection;
1 trial17 (n = 191) compared the
delayed prescribing strategy with immediate prescribing, leaving it uncertain
whether either approach was preferable to no offer of antibiotic treatment,
which has been advocated strongly.18 A recent
Cochrane review19 of delayed prescribing argued
for more evidence and, in particular, better reporting of symptomatic outcomes.

The relative importance of prescribing strategies and information about
natural history is also unclear. Preliminary evidence suggests that provision
of an information leaflet can affect return rate and antibiotic use in lower
respiratory tract infection,20,21 although
the effect on symptomatic management of such a simple leaflet and whether
a leaflet provides additional benefit to simple verbal information remains
unclear.

Our goals were to assess the effectiveness on symptoms, beliefs, and
behavior of 3 different antibiotic prescribing strategies and assess the effectiveness
of an information leaflet compared with brief verbal information alone.

METHODS

Inclusion Criteria

We recruited patients aged 3 years or older with uncomplicated acute
illness (≤21 days) who presented in primary care with cough as the main
symptom and with at least 1 symptom or sign localizing to the lower tract
(sputum, chest pain, dyspnea, wheeze). Our criteria used the same criteria
as previous large cohorts in England of patients with lower respiratory tract
infection.22,23

Exclusion Criteria

We excluded patients with a history and physical examination suggestive
of pneumonia based on the British Thoracic Society guidelines,24 which
included new focal chest signs (focal crepitations or bronchial breathing)
and systemic features (high fever, vomiting, severe diarrhea). Because there
is no clear agreement among the clinical prediction rules that have been used
to exclude pneumonia11,12,14,25 and,
although C reactive protein (CRP) may help predict pneumonia, most physicians
in England rarely use CRP in the assessment of acute infections.11,12,26 We
also excluded patients clinically diagnosed with asthma; other chronic or
acute lung diseases, including cystic fibrosis, cardiovascular disease, major
current psychiatric diagnosis, mental subnormality, and dementia; or with
complications from previous episodes of lower respiratory tract infection
(eg, hospital admission for pneumonia).

Sample Size

Using our pilot data,27 for the immediate
antibiotic prescribing strategy to make an SD difference of approximately
0.3 in the severity of symptoms or duration of cough (SD of 0.3 equals 1-2
days), we required at least 162 patients per antibiotic prescribing group,
or 486 diary returns (for α = .05, β = .20).
A total of 800 patients allowed us to detect an 11% difference in reconsultation
rates.16 Our study was approved first by the
South West Multi Centre Research Ethics Committee (whole region of South West
England), and by each local research ethics committee (Southampton, Salisbury,
Winchester, Portsmouth, and Bristol).

Randomization

After written informed consent, 807 patients were randomized. Randomization
was required within the consultation to make the prescribing strategies feel
the most natural to patients. Sealed opaque numbered envelopes containing
structured advice for 1 of the 6 groups were prepared several weeks in advance
at the study center by the research team by using computer generated random
number tables, and block randomization (block size 6) was used to minimize
significant group size discrepancies. Recruiters were not told that block
randomization was being used, and different recruiters in each practice took
individual envelopes from the same source.

Patients were assigned to 1 of 6 groups by a factorial design. The first
factor randomized patients to leaflet or no leaflet, and the second factor
randomized patients to 1 of 3 antibiotic groups (immediate antibiotics, no
offer of antibiotics, and delayed antibiotics). Delayed antibiotics was defined
as advice to use a course of antibiotics available on request if symptoms
were not resolved after 14 days.

The antibiotics prescribed to the patients were 250 mg of amoxicillin
3 times per day for 10 days (125 mg if aged ≤10 years) or 250 mg of erythromycin
4 times per day if allergic to penicillin. These doses were chosen based on
the British National Formulary recommendations for uncomplicated infection
and from the evidence of community studies in England before and during the
study that indicated no resistance among streptococcal isolates.22,23

In the delayed antibiotic group, the prescription was written at the
time of the initial consultation and left in a box at reception. The decision
to collect the script was left to the discretion of the patient or parents
(if the patient was age <16 years) without requiring a further appointment,
which we have shown to be feasible with high compliance.15 Although
patients were advised to wait 14 days, they could request antibiotics earlier.

For each group, a small number of statements were read by the physician,
which included advice to take analgesics, the likely natural history of the
illness, and supporting the proposed prescribing strategy. This generated
a placebo effect in each group.15 The physician
checked a box when each statement was read, documented clinical signs, and
mailed the documentation back to the study center.

All patients, irrespective of whether they had the leaflet, were given
brief verbal information about the likely range of natural history.20 The leaflet was simple, only 1 page, and included
information about the natural history.21,28 It
also addressed patients’ major worries28 and
provided advice about when to seek further help (eg, persistent fever, worsening
shortness of breath).

Outcome and Data Collection

Daily Diary and Satisfaction Questionnaire. Patients,
or with parents’ help if younger than 16 years, completed a validated
daily symptom diary (available on request). They also recorded their temperature
with single-use disposable thermometers (3M Tempa-DOT, 3M Corporate, St Paul,
Minn), where the dots change color and can be read to within 0.1°C.27 The recorded diary items included antipyretic use
and 6 symptoms (cough, dyspnea, sputum production, well-being, sleep disturbance,
and activity disturbance). Each of the 6 symptoms were scored (0 = no
problem, 1 = very little problem, 2 = slight problem,
3 = moderate problem, 4 = bad problem, 5 = very
bad problem, and 6 = as bad as it could be). Patients also completed
Likert scales of how satisfied or concerned they were with different aspects
of treatment (6-point scale: extremely satisfied, very satisfied, moderately
satisfied, slightly satisfied, not very satisfied, and not at all satisfied).
These Likert scales have previously been shown to be reliable, have good construct
validity, and predict illness duration.15,29 Patients
also rated their belief in antibiotics using a 6-point scale (extremely effective,
very effective, moderately effective, slightly effective, not very effective,
and not at all effective).

Clinical Symptoms and Signs. The clinical history,
symptoms (prior duration, sputum production, sputum color), signs (breath
sounds: normal or bronchovesicular), or added sounds (crepitations, wheeze)
were documented initially by the physician. Physicians were not provided with
any special training, given that the examination of the chest is part of daily
routine clinical practice.

Reported Antibiotic Use. Because prescription
redemption is not necessarily a guide to prescription use, we asked patients
to document whether they used antibiotics and for how many days (giving patients
the permission not to comply but not encouraging noncompliance). We have previously
shown that reported antibiotic use, documented by a self-completed questionnaire
after the diary was completed, is very reliable when validated against prescription
collection.15

Notes Review. The patients’ notes were
reviewed by an author (J.K.) who was blind to study group for reconsultation
with cough and for complications within 1 month after randomization. The advantage
of England’s primary care system is that all patients are registered
with their primary care physician (private practice is rare), which means
that contacts for review of illness will be documented in the note of the
registered practice.

Statistical Analysis

We used analysis of variance and logistic regression for a factorial
study for continuous and dichotomous outcomes, respectively. All patient data,
where outcomes were available and with no imputation of missing values, were
analyzed according to the randomized group in an intention-to-treat analysis.
We first tested for interactions between factors. Because no interactions
were found, main effects for each factor are presented that mutually control
for the effect of each factor. For the number of reattendances with cough
in the month after the physician visit, which follows a Poisson distribution,
we used Poisson regression for a factorial study. Stata software version 7
(StataCorp LP, College Station, Tex) was used for all statistical analyses. P ≤.05 was considered statistically significant.

RESULTS

Recruitment

Thirty-seven physicians in England (mainly around Southampton and Bristol)
were recruited during a 5-year period (August 18, 1998, to July 30, 2003)
and 807 patients were recruited from the same area (Figure 1). Although most physicians only approached a few patients
(lack of time being the most common reason), the 4 highest recruiting physicians
recruited the majority of the patients (540 patients [67%], most of the patients
presented to the physician). Recruitment status of patients (from high vs
low recruiting physicians) did not predict any outcome. There was no evidence
of any significant interaction between recruitment status and the effectiveness
of prescribing antibiotics immediately; the estimates of the interaction were
small (for the mean diary score, 0.25; 95% confidence interval [CI], −0.20
to 0.71; for mean duration of moderately bad cough, 1 day; 95% CI, –0.76
to 2.76 days; and for mean duration of any moderately bad symptom, 0.55 days;
95% CI, –1.60 to 2.70 days).

Figure 1. Flow of Patients Through Trial

*Eligible patients approached for inclusion in the trial were estimated
from physician self-report.

Baseline Characteristics

We recruited 136 patients (17%) who were children (<16 years) and
133 older patients (17%) (>60 years). As expected, children presented with
higher temperatures (mean temperature, 36.9°C [SD, 0.7°C]), with 51%
having an axillary temperature of at least 37.0°C; for adults, the mean
temperature was 36.6°C (SD, 0.7°C).

Baseline clinical characteristics were similar in the intervention groups
(Table 1). The severity of symptoms
was the primary outcome, which was close to being significantly different
by group; however, the adjusted estimates for severity of symptoms including
all baseline variables in the model were –0.05 for leaflet vs no leaflet
(P = .58), –0.02 for delayed vs no
antibiotics (P = .86), and –0.07
for immediate vs no antibiotics (P = .49).
This suggests adequate control of confounding by randomization.

Loss to Follow-up for Symptom Resolution

A total of 562 patients (70%) returned complete diaries after 3 weeks
and an additional 78 (10%) provided information about both symptom duration
and severity. There were no differences in baseline characteristics (eg, fever,
sputum, chest signs) comparing those patients followed up to those not followed
up. Those patients not followed up had low return rates in the next month
(6% vs 15% for those followed up), which suggests they were not likely to
have had severe illness.

Symptom Duration and Severity

Main results are shown in Table 2 and Table 3; descriptive information for cumulative
duration of symptoms is shown in Figure 2.
There was no effect of the leaflet on any primary outcome. Cough that was
rated at least “a slight problem” lasted a mean of 11.7 days (25%
of patients had a cough lasting ≥17 days), and a moderately bad cough lasted
a mean of 6.0 days (25% of patients had a cough lasting ≥8 days). Compared
with no offer of antibiotics, other prescribing strategies did not alter the
primary outcomes (Table 2). Antibiotics
reduced duration of moderately bad symptoms (scoring ≥4 of 6 on any symptom
each day) by 1 day overall and reduced moderately bad symptoms for 4 individual
diary items, but in all cases making less than 1 day difference for phlegm
(mean, −0.96 days; 95% CI, −1.84 to −0.08), sleep disturbance
(mean, −0.73 days; 95% CI, −1.46 to 0.00), activity disturbance
(mean, −0.93 days; 95% CI, −1.72 to −0.13), and feeling
unwell (mean, −0.91 days; 95% CI, −1.71 to −0.11).

Table Graphic Jump LocationTable 2. Estimates in Control Group of Each
Factor and the Estimated Mean Differences Due to Interventions in Each Factor

Figure 2. Duration of Cough After Physician
Visit Until Patient Is Feeling Better

Feeling better was defined as a cough that was rated very little or
no problem. The cumulative percentage of patients who are better after the
physician visit in the 3 antibiotic-prescribing groups is shown (by day 11,
50% of patients were better and by day 19, 80% were better no matter what
prescribing strategy was used).

Satisfaction, Beliefs, and Antibiotic Use

Slightly fewer patients were very satisfied, fewer used antibiotics,
and fewer believed in the effectiveness of antibiotics in the delayed and
control groups vs the immediate antibiotic group (Table 3).

Adverse Events

One patient in the no antibiotic group developed pneumonia, was admitted
to the hospital, administered antibiotics, and recovered fully. Diarrhea was
slightly more common but not significantly in the delayed groups (odds ratio
[OR], 1.17; 95% CI, 0.67-2.03; P = .58)
and the immediate group (OR, 1.22; 95% CI, 0.70-2.12; P = .48).

Subgroups

A priori, we defined patients with colored sputum and elderly persons
aged at least 60 years as possible subgroups who might preferentially benefit
from the offer of immediate antibiotics.7,30

There was no evidence of a significantly different effect for those
patients with colored sputum for duration of cough (interaction terms for
delayed group, −0.09 days; 95% CI, −3.67 to 3.47; P = .96; interaction term for immediate antibiotic group,
−1.85 days; 95% CI, –5.51 to 1.81; P = .32).

Elderly patients had shorter symptom duration (−2.65 days; 95%
CI, −4.78 to −0.62; P = .01)
and also benefited less from either delayed antibiotics (interaction term,
3.59 days; 95% CI, 0.64-6.53; P = .02)
or immediate antibiotics (interaction term, 2.84 days; 95% CI, 0.005-5.67; P = .05). These results were not affected by
controlling for baseline clinical characteristics. There was no evidence for
a differential effect in children, either in terms of symptom duration or
effect of prescribing strategies on outcome.

Patients with asthma at presentation were excluded, but some patients
were given a clinical diagnosis of asthma during follow-up. Excluding 33 (5%)
of 691 patients who had a diagnosis of asthma made in the subsequent 12 months
did not alter the estimates of effect size on duration of cough for immediate
antibiotics (interaction term, 0.14 days; 95% CI, –1.01 to 1.29).

COMMENT

To our knowledge, our trial is the largest randomized trial of antibiotic
use for lower respiratory tract infection presenting in primary care and provides
important information for management, being a similar size to the data set
for the existing Cochrane systematic review,7 but
also suggests a smaller effect of antibiotics.

Our study had several limitations. There is no widely agreed definition
of lower respiratory tract infection7; therefore,
we used the criteria from previous large cohorts22,23 to
define our study population and, in practice, most patients in this cohort
had acute cough with sputum.

An open design was essential in our study to allow the observance in
practice of the pragmatic uptake and effect of prescribing strategies on such
outcomes as beliefs and antibiotic use. The limitation of our design is the
possibility of a placebo effect favoring antibiotics. However, any differential
placebo effect was minimized by the physician using a structured approach
to support each strategy. There was no evidence of a differential placebo
effect using the same approach in the previous trial in upper respiratory
tract infection.15 In our study, little evidence
of a placebo effect was observed favoring immediate antibiotics for the main
outcome measures.

Our study confirms the long natural history of lower respiratory tract
infection, in that patients need to be warned that they will on average have
an illness lasting 3 weeks in total with 10 days of symptoms before the physician
visit and 12 days after the physician visit.

Compared with immediate antibiotics, a strategy of either no offer of
antibiotics or delayed prescribing is associated with little difference in
duration or severity of symptoms. This is consistent with recent existing
systematic reviews and suggests that for most patients, antibiotics probably
provide modest symptomatic relief.7,8 The
estimates from our study suggest that the likely effect sizes of prescribing
immediate antibiotics in routine practice are likely to be rather more modest
than documented in the Cochrane review.7

A secondary finding from our study was that immediate antibiotics may
possibly reduce the duration of moderately bad symptoms. This must be interpreted
with caution as it is a secondary finding. Even if this finding is not due
to type I error, it represents benefit of only 1 day in an illness with a
relatively long natural history. It is difficult to justify widespread antibiotic
prescribing for uncomplicated lower respiratory tract infection on this basis
given the dangers of antibiotic resistance.31,32

Other important findings of our study were that although 10% fewer of
our patients were very satisfied, not offering antibiotics or using delayed
prescribing are both very acceptable to most patients, which supports previous
evidence about the modest differences in satisfaction when antibiotics are
prescribed33; and there are likely to be reductions
in both belief in antibiotics and antibiotic use, with delayed prescribing
performing almost as well as no initial offer of antibiotic use. The low prescription
use for the collection approach to delayed prescribing used in our study is
similar to the finding in upper respiratory tract infection,15 but
may well be lower than rates of delayed prescription use in which the patient
is given the prescription to take away.34 Our
study suggests that one advantage of immediate or delayed antibiotics is fewer
reattendances with cough in the month after the physician visit.

The lack of effect of an information leaflet does not mean that leaflets
are unhelpful because previous evidence suggests that they are helpful,20,21 but that there is no reinforcing
effect of a leaflet beyond providing verbal information, which all patients
in our study were given. The 14% decrease in antibiotic use with a leaflet
among those patients who received a delayed antibiotic prescription reported
previously20 occurred when the delayed prescription
was given to the patient and antibiotic use was high (49%-63%). In contrast
with our study in which patients were asked to collect their prescription
if they wished to use it, antibiotic use was much lower, which may have limited
the power of our study to detect an information-leaflet effect. The finding
of increased attendance during the following month probably reflects patients
responding to advice in the leaflet to reattend for particular circumstances,
such as ongoing fever or shortness of breath.

In conclusion, in our patients from primary care who presented with
acute uncomplicated lower respiratory tract infection, the use of delayed
antibiotics or no antibiotics was acceptable, resulted in little difference
in duration or severity of symptoms compared with immediate treatment with
antibiotics, and considerably reduced both antibiotic use and belief in antibiotics.
These findings suggest that adopting these strategies would help limit the
vicious circle of the medicalization of self-limiting illness when antibiotics
are prescribed. Immediate antibiotic prescribing is likely to limit the number
of patients who return for cough within the next month but only by a little
more than delayed antibiotic prescription. The challenge now is for clinicians
and researchers to determine which groups are at risk of adverse outcomes
and identify those patients who might selectively benefit from immediate antibiotic
prescription.

Financial Disclosures: Dr Little has received
consultancy fees for 2 half days from Abbott Pharmaceuticals regarding complications
of respiratory infections. Mr Watson was previously employed by the University
of Southampton and is now currently an employee of GlaxoSmithKline. No other
authors reported financial disclosures.

Funding/Support: This study was supported by
the Medical Research Council.

Role of the Sponsor: The Medical Research Council
did not participate in the design and conduct of the study, in the collection,
analysis, and interpretation of the data, or in the preparation, review, or
approval of the manuscript.

Acknowledgment: We are grateful to the patients
who agree to participate in this study and to the physicians who recruited
them. We thank Peter Smith, PhD, for the fitting of the Poisson regression
model.

Melbye H, Aaras I, Fleten N, Kolstrup N, Mikalsen J. The value of C-reactive protein testing in suspected lower respiratory
tract infections: a study from general practice on the effect of a rapid test
on antibiotic research and course of the disease in adults. Tidsskr Nor Laegeforen. 1995;115:1610-1615PubMed

Figure 2. Duration of Cough After Physician
Visit Until Patient Is Feeling Better

Feeling better was defined as a cough that was rated very little or
no problem. The cumulative percentage of patients who are better after the
physician visit in the 3 antibiotic-prescribing groups is shown (by day 11,
50% of patients were better and by day 19, 80% were better no matter what
prescribing strategy was used).

Melbye H, Aaras I, Fleten N, Kolstrup N, Mikalsen J. The value of C-reactive protein testing in suspected lower respiratory
tract infections: a study from general practice on the effect of a rapid test
on antibiotic research and course of the disease in adults. Tidsskr Nor Laegeforen. 1995;115:1610-1615PubMed

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